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AT A GLANCE
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Traumatic brain injury at a glance AT A GLANCE
Neurochemical changes associated with TBI including changes in glucose metabolism, free radical production
Normal transmission of signals involves neurotransmitter-mediated and mitochondrial dysfunction.
activation of receptors and subsequent controlled ionic changes in
the postsynaptic membranes of neurotransmitter-releasing cells. Changes in cerebral glucose metabolism in TBI
Ionic changes across the bilipid membrane are meticulously Glucose is the primary fuel source of the adult brain and its
regulated by energy-dependent sodium-potassium (Na+-K+) processing through the glycolytic pathway provides carbons for the
ATPase pumps, which maintain the membrane potential between tricarboxylic acid (TCA) cycle for energy production in the form
−40 and −70 mV (Katsura et al., 1994). TBI induces transient cell of ATP. Changes in cerebral glucose metabolism (CMRglc) have
membrane disruptions that lead to redistribution of ions and been established as a hallmark response after TBI. Two chemical
neurotransmitters, altering the membrane potential (see poster, isotopes (18F-DG and 14C-2DG) are frequently used to measure
Disease Models & Mechanisms DMM
panels B and C). During the acute phase (≤1 hour) after TBI, there glucose uptake (transport) into the brain. Glucose analogs are
is a massive release of glutamate from presynaptic terminals, which metabolized by the enzyme hexokinase, which is the first enzyme
disrupts ionic equilibrium on postsynaptic membranes. The in the glycolytic pathway (see poster, panel D). Once these isotopes
amount of potassium (K+) released increases with injury severity, are cleaved by hexokinase they become trapped in the cells, which
as measured by microdialysis (Katayama et al., 1990; Kawamata et allows the accumulation of glucose to be measured.
al., 1992). In these early studies, mild FP injury produced a 1.4- to Autoradiographic images are generated to look at regional changes
2.2-fold increase in extracellular [K+] levels that was blocked by in isotope-glucose uptake, which can be quantified according to
tetrodotoxin (a neurotoxin that prevents brain cell firing), the density of the gray scale. Darker regions reflect greater glucose
suggesting that this rise in [K+] is related to neuronal firing. More uptake and whiter regions reflect lower glucose uptake (see poster,
severe injuries produced greater increases (4.3- to 5.9-fold) in [K+] panel E). These isotopes have been used to show a rapid increase
that were tetrodotoxin-resistant. Administration of kynurenic acid, in glucose uptake followed by a prolonged period of glucose
an antagonist of excitatory amino acids, attenuated the [K+] metabolic depression, as observed in both experimental and clinical
increase in a dose-dependent manner, suggesting that the K+ surge head injury (Yoshino et al., 1991). Following FP injury in adult rats,
is dependent on excitatory neurotransmitters. In order for brain the early transient increase in CMRglc can be detected 30 minutes
cells to fire again, ionic equilibrium must be re-established, which post-injury and it has been shown that this can be attenuated by
requires ATP (cellular energy). administration of kynurenic acid (Kawamata et al., 1992). It has
In addition to rising [K+], calcium (Ca2+) accumulation is also been proposed that this initial increase in CMRglc is due to an
commonly observed after TBI (Osteen et al., 2001). Accumulation increased requirement of cellular energy to restore the ionic
of intracellular Ca2+ activates mitochondrial Ca2+ uptake. Ca2+ balance and neuronal membrane potential (Hovda et al., 1990;
overloading of the mitochondria has been shown to induce oxidative Hovda et al., 1991; Hovda et al., 1996). This acute period of
stress and to impair mitochondrial function (Xiong et al., 1997; Peng ‘hyperglycolysis’ has been observed within the first 8 days after
and Jou, 2010). To determine the effects in the context of TBI, severe human head injury (Bergsneider et al., 1997).
accumulation of isotope-labeled Ca2+ (45Ca2+) was measured in adult The acute period of increased CMRglc is followed by a prolonged
rats after FP injury. Increases in 45Ca2+ were seen as early as 6 hours period of decreased CMRglc. This decrease in CMRglc has been
after the initial injury, and a return to control levels has been observed observed in experimental models of FP and CCI (Andersen and
between 4 days (Fineman et al., 1993) and 7 days (Deshpande et al., Marmarou, 1992; Yoshino et al., 1991; Kawamata et al., 1992;
2008) post-injury. Ca2+ accumulation corresponded with the presence Richards et al., 2001; Chen et al., 2004), and has also been
of cognitive deficits, which were detected using the spatial memory documented in human TBI (Bergsneider et al., 2000; O’Connell et
task, the Morris water maze. The surge in Ca2+ and the cognitive al., 2005). In the experimental models, the magnitude and duration
problems both recovered by 30 days post-injury (Deshpande et al., of this glucose metabolic depression were found to increase with
2008; Sun et al., 2008). Whereas the influence of animal age on injury severity. Glucose metabolic depression was maintained for 5,
glutamate and K+ changes have not been determined after injury, 10 or 14 days after mild, moderate or severe FP injury in adult rats,
age effects on the pattern of acute 45Ca2+ accumulation have been respectively (mild and moderate are shown in panel E of the poster)
observed, with younger animals showing faster normalization after (Hovda et al., 1994). CCI injury has been found to induce a more
injury and delayed secondary increases associated with cell death profound and longer-lasting depression in the penumbra (area
compared with older animals (Osteen et al., 2001). In summary, TBI adjacent to the core of cells that will die) than does FP injury (Sutton
gives rise to early ionic and neurotransmitter perturbations that et al., 1994; Prins and Hovda, 2009). Consistent with the experimental
initiate a cascade of events that disrupt normal cellular function, model data, global cortical CMRglc depression was found to be
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AT A GLANCE Traumatic brain injury at a glance
greater in severely injured TBI patients, although this was not closely Another reason for decreased glucose uptake after TBI could be
associated with levels of consciousness (Bergsneider et al., 2000). related to impaired glucose transport through the blood vessels and
However, glucose metabolic rates in the thalamus, brain stem and into brain cells. Adult rat studies have shown decreased neuronal
cerebellum significantly correlated positively with the levels of glucose transporter (GLUT1) immunoreactivity 2-4 hours after FP
consciousness, as measured by the GCS (Hattori et al., 2003). injury (Balabanov et al., 2001); however, the expression of this
Age-related differences in the magnitude and duration of CMRglc neuronal glucose transporter is patchy in clinical cases of TBI, i.e.
depression have been demonstrated in experimental models of TBI regions with increased and decreased expression are present
(see poster, panel F). Specifically, the duration of glucose metabolic (Cornford et al., 1996). Hattori et al. examined the 18F-DG kinetic
depression increases with age. FP-injured postnatal day (PND) 17 changes following moderate to severe TBI in humans and
juvenile rats show glucose metabolic recovery to the level of age- determined that hexokinase activity was globally decreased, with
matched control animal (sham) levels within 3 days (Thomas et al., glucose transport impairments occurring specifically within the
2000), whereas recovery takes approximately 10 days in adult rats. contusion sites (Hattori et al., 2003). Collectively, the studies
In the diffuse injury model, adult-like patterns in glucose metabolism indicate that glucose transport across the blood-brain barrier is
depression are achieved during adolescence (Prins and Hovda, substantially affected by TBI in both animal and human brains.
2001). Following CCI in the adolescent rat (PND 35), the metabolic Finally, decreases in cerebral glucose levels could reflect problems
rates in subcortical and cortical structures recover within 3 or 5 days, with glucose metabolism within the cell. There is increasing
respectively (Prins and Hovda, 2009). A longer-lasting glucose evidence that the glycolytic processing of glucose is affected by
metabolic depression was observed in the cortex among PND 75 trauma. Following CCI injury, glucose metabolic processing was
(adult) rats with CCI injury, as shown in the poster (panel F). In determined with [1,2 13C]-labeled glucose infusion (Bartnik et al.,
general, the younger animals seem to show faster reversion of glucose 2005). Proton nuclear magnetic resonance (NMR) spectroscopy
Disease Models & Mechanisms DMM
metabolic depression. In humans, there has only been one study that revealed a 9-12% increase in the level of glucose that is shunted
examined glucose uptake after TBI in the pediatric brain (4 months towards synthesis of pentoses (used in the synthesis of nucleic acids)
to 19 years of age), but young and adolescent children were not via the pentose phosphate pathway at 3.5 hours and 24 hours post-
compared with each other or with adults (Worley et al., 1995). injury (see poster, panel D). Furthermore, nicotinamide
dinucleotide (NAD+) concentrations have been shown to decrease
Comparison of glucose metabolic changes in TBI between different
after injury (Vagnozzi et al., 1999; Satchell et al., 2003), which could
age groups within the pediatric population, or a comparison between
be at least partly attributable to increased consumption by a DNA
adults and children, has not yet been made in humans. Regardless
repair enzyme, as described in the subsequent section. NAD+ is a
of age, the prolonged glucose metabolic depression reflects a period
necessary cofactor for the glycolytic enzyme GAPDH
of time during which glucose uptake into the brain is compromised.
(glyceraldehyde 3-phosphate dehydrogenase), so reductions in
This could cause downstream negative effects if the energy demands
NAD+ levels can cause glycolytic inhibition (Sheline et al., 2000).
of the brain are not sufficiently met.
Pyruvate dehydrogenase (PDH) is the enzyme that connects the
glycolytic pathway to the mitochondrial TCA cycle.
Post-TBI energy crisis: causes and consequences Phosphorylation of the E1 subunit of PDH, which inhibits PDH
Although decreased glucose uptake after injury seems to be a function and therefore carbon entry into the mitochondria, has
universal response, the underlying mechanism remains unknown. been shown to occur at a higher frequency than normal at 24 hours
There are three possibilities: decreased blood availability [which after CCI injury (Xing et al., 2009). These TBI-induced alterations
depends on cerebral blood flow (CBF)], defects in glucose in glycolytic enzyme functioning ultimately decrease the ability of
transporter function or decreased metabolic demand for glucose. glucose to be efficiently processed for oxidative metabolism, and
The rapid increase in CMRglc immediately after injury reflects an thereby contribute to the post-TBI energy crisis, reflected by
acute period of increased glucose consumption (as outlined above) reductions in ATP production (see poster, panel D).
and this occurs during a time when CBF has been shown to decline
(Golding et al., 1999). In an earlier study, the adult rat brain showed The role of free radicals in TBI
a 52% decrease in cortical CBF within 15 minutes of FB injury, and Increased generation of free radicals is another factor that
the level remained significantly low for 4 hours, with recovery contributes to the TBI-induced metabolic crisis. Free radicals are
occurring at 24 hours post-injury (Yamakami and McIntosh, 1991). molecules with unpaired electrons. These compounds are highly
Two hours after weight-drop injury, Grundl et al. observed reactive because they attempt to gain electrons from surrounding
decreases in CBF in both immature and mature animals (Grundl substances, which can result in cell membrane, protein and DNA
et al., 1994). During this acute phase, when CBF does not meet the damage (see poster, panel D). There are two main families of free
cerebral metabolic needs of the tissue, this mismatch or radicals: reactive oxygen species (ROS) and reactive nitrogen
‘uncoupling’ can initiate cascades of secondary injury events and species (RNS). Production of O2– is a consequence of normal
energy crisis. So, do these CBF changes limit glucose availability? metabolism, and this species is a precursor to hydrogen peroxide
Plasma glucose levels in head injury patients are difficult to (H2O2), which can generate hydroxyl radicals (•OH) via the Fenton
determine, because the levels are carefully maintained within reaction. The •OH is one of the most reactive chemical species.
specific ranges (Vespa et al., 2006). Experimental studies in both Reaction of O2– with nitric oxide (NO•) produces peroxynitrite
immature and mature rats did not reveal significant changes in (ONOO–). Normal metabolic activities produce levels of ROS that
plasma glucose supply after TBI and did not suggest substrate are well managed by cellular antioxidant defense systems. It is only
limitation (Prins and Hovda, 2009). after cerebral injury that the levels of ROS production overwhelm
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Traumatic brain injury at a glance AT A GLANCE
scavenging systems and result in oxidative damage (O’Connell and and double DNA strand breaks, and its activity has been shown to
Littleton-Kearney, 2013; Kerr et al., 1996; Hall and Braughler, 1993). increase after various types of brain injury. Pathological activation
Mitochondria are a source of free radical generation. During of PARP has been shown to decrease cytosolic NAD+ pools, to
normal metabolism, the TCA cycle generates reducing equivalents inhibit glycolytic processing of glucose and to decrease ATP
to produce ATP. Electrons are normally transferred along the production (Cipriani et al., 2005; Alano et al., 2010). Evidence of
electron transport chain, with only 1-2% of the oxygen generating PARP hyperactivation in ischemia and the demonstrated
oxygen radicals at Complex I in the respiratory chain. However, neuroprotective potential of PARP inhibitors encouraged research
following TBI, changes in the availability of these reducing into the role of PARP in TBI. Satchell et al. reported elevation in
equivalents is diminished and the production of O2– is increased. PARP1 (a subtype of PARP enzymes) activity 8 hours after CCI
Concomitantly, TBI-induced intracellular Ca2+ accumulation can injury (Satchell et al., 2003). This activity level remained significantly
activate numerous enzymes, including xanthine dehydrogenase, greater than that in controls for 21 days post-injury. Inhibition of
phospholipase A2 and nitric oxide synthase (NOS), which increase PARP activity decreased the lesion size at 24 hours after FP injury,
O2– and NO• production (Lewén et al., 2000). but did not decrease the number of apoptotic cells (LaPlaca et al.,
Despite the short-lived nature of free radicals, their production 2001). Partial PARP1 inhibition after CCI injury preserved cellular
has been quantified after brain injury. In severely injured mice, NAD+ concentrations and improved functional performance in the
hydroxyl radical (•OH) production increases 60% within the first Morris water maze (Satchell et al., 2003).
minute, peaks at 30 minutes after injury and subsequently decreases Although age-dependent effects on free radical production or
(Hall et al., 1993a; Hall et al., 1993b). In contrast with this transient consequent damage in TBI have not been studied in depth, age-
period of •OH formation, severe CCI-injured rats showed a 250% related differences in antioxidant defense systems have been
increase in •OH production, which was sustained above baseline examined. After CCI injury, glutathione peroxidase (GPx) activity
for 90 minutes (Marklund et al., 2001). A similar pattern in •OH
Disease Models & Mechanisms DMM
increased ROS production in isolated cortical synaptosomes injury (Fukushima et al., 2009), and this treatment also improves
(Sullivan et al., 1998; Sullivan et al., 1999). Long-lasting changes in neurobehavioral recovery (Moro and Sutton, 2010; Moro et al.,
mitochondrial respiration have also been reported following CCI 2011). In addition to these monocarboxylates, ketones have also
injury (Xiong et al., 1997). TBI induced a significant reduction in been shown to confer neuroprotection when provided as an
oxidative phosphorylation at 1 hour post-injury; this decrease alternative fuel source after TBI. Administering the ketogenic diet
persisted for 14 days. In the ipsilateral cortex, greater mitochondrial after CCI injury reduced cortical contusion volumes, improved
Ca2+ accumulation and lower ATP production were observed. motor and cognitive function, and alleviated cellular ATP
Recurring mitochondrial impairments result in activation of both reductions in the adolescent rat brain (Prins et al., 2005; Prins, 2008;
apoptotic and necrotic pathways, contributing to cell death (Lewén Prins et al., 2010; Appelberg et al., 2009; Deng-Bryant et al., 2011).
et al., 2001; Robertson, 2004). Ketosis has also been shown to decrease cytochrome c release and
Alterations Ca2+ in mitochondrial energy metabolism have also levels of markers of apoptotic cell death after CCI injury in the
been described in the immature rat. TBI resulted in uncoupling of juvenile rat (Hu et al., 2009a; Hu et al., 2009b). The fasting of adult
respiration within 1 hour after injury and significant decreases in animals has also been used to induce ketosis, which has been shown
mitochondrial respiration by 4 hours after injury (Robertson et al., to decrease oxidative stress and Ca2+ loading, and to improve
2007). Several age-associated differences in expression of proteins mitochondrial oxidative phosphorylation at 24 hours post-CCI
involved in mitochondrial energy metabolism and cell death injury (Davis et al., 2008).
pathways exist. For example, the electron transport chain proteins Addition of ethanol pyruvate to cerebrocortical slices exposed to
II, III and IV reach adult expression levels within the first few oxidative stress alleviated ATP decreases and improved cell survival
months of life, whereas the proteins I and V reach adult expression (Zeng et al., 2007). Pyruvate also improved ATP depression, alleviated
levels within 2 weeks of birth (Bates et al., 1994). Respiration- GAPDH inhibition and prevented cell loss in hippocampal
dependent Ca2+ uptake is also influenced by age. In mitochondria
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Traumatic brain injury at a glance AT A GLANCE
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